Immediate or Type 1 allergic reactions generally occur, in susceptible humans and animals, immediately following contact with an antigen, which is referred to as the allergen. Such reactions may have long term consequences. Type I allergic reactions are largely attributed to IgE antibodies, although IgG antibodies can participate in and modulate them (Dombrowicz et al, 1998; Ujike et al, 1999). An allergic reaction is generally caused by the activation of a subpopulation of immune cells, the mast cells and basophils. When an antigen reacts with IgE antibody receptors on the surface of a cell, chemical mediators initiate the allergic reaction by acting on adjacent immune, epithelial, endothelial and smooth muscle cells and promote, in a longer term, the influx of other inflammatory and immune cells (neutrophils, eosinophils, monocytes, lymphocytes) into the affected tissue. This influx of inflammatory cells predisposes the patient to recurrent, and sometimes delayed or prolonged, allergic or hypersensitivity reactions and is frequently associated with non-reversible remodeling of the tissue. Type 1 allergic reactions are identified according to the location in which they occur, e.g. asthmatic reactions occur in the lungs, rhinitis in the nose, conjunctivitis in the eyes, atopic dermatitis in the skin, systemic allergic reactions in the circulation and intestinal reactions in the gastrointestinal system.
Asthma can be defined clinically as a condition of intermittent, reversible airways obstruction; asthma manifests itself as several clinical entities: allergic asthma, bronchial asthma, exercise induced asthma (EIA), chemical induced asthma, and status asthmaticus. Asthma can be divided into two types. Extrinsic asthma is generally triggered by external agent such as allergens (dust mites, pollen, stings, drugs, or foods), and is commonly diagnosed in early life. Intrinsic asthma, which is allergic-like and generally develops later in life, can be triggered by congested and inflamed tissues, infection, common cold viruses (RSV, parainfluenza, rhinovirus), endogenous catecholamines (e.g. adrenaline), drugs (e.g. aspirin), cold air, stress or exertion, various irritants (cigarette smoke, burning leaves, perfumes, strong odors) and some food intolerance. Intrinsic asthma occurs without the participation of an allergic trigger by specific antibodies against an allergen.
Bronchial asthma is usually a chronic (long-term) disease affecting the bronchial tubes (bronchi and/or airways) of the lungs. The symptoms of asthma are the result of constriction or narrowing of irritable bronchial tubes resulting in wheezing and difficulty in breathing. This constriction of the airways, caused by bronchial tube muscle spasm and narrowing due to inflammation, is most frequently provoked by antigen-induced release of histamine, leukotrienes and other chemical mediators from mast cells. With intrinsic asthma, these mediators are released without an allergic trigger. The net result of the asthmatic attack is muscle spasm, inflammation, edema (swelling), and increased mucus production within the bronchi. Both extrinsic and intrinsic asthmatic reactions generate symptoms within 15–30 minutes of exposure (immediate response) which generally subside within an hour. In some individuals, a delayed response (late phase reaction) occurs 3–4 hours following the immediate or initial response. It should be noted, however, that the timing of these reactions exhibits marked variability between patients and can be shorter or longer in onset and duration. The late phase reaction, which probably develops from an inflammatory reaction, may last many hours or days and is frequently associated with increased bronchial hyperreactivity or persistent airway hyperresponsiveness. As a consequence, the bronchioles become irritable and hyperresponsive, rendering the individual more sensitive to a variety of inhaled irritants other than the allergen.
Rhinitis, allergic conjunctivitis and atopic dermatitis are inflammations of the nasal mucosa, eyes and skin, respectively, often due to allergens such as pollen, dust or other airborne substances.
Anaphylactic shock, the most severe form of allergy, is a medical emergency. It is often severe and can sometimes provoke a fatal systemic reaction in a previously sensitized human or animal upon exposure to a specific antigen, such as nuts, wasp or bee venom or penicillin. Anaphylactic shock is characterized by respiratory symptoms, fainting, itching, urticaria, swelling of the throat or other mucous membranes and/or a sudden decline in blood pressure. Symptoms of anaphylactic shock include dizziness, loss of consciousness, laboured breathing, swelling of the tongue, blueness of the skin, bronchospasm, low blood pressure, and death. Anaphylactic reactions can also cause modification of heart function and are associated with an increase in neutrophil influx into the heart tissue (Turesin et al, 2000). This inflammation of the heart is effected by the leukocyte adhesion cascade.
For the most part, the available drugs for treating asthma block or neutralize the effects of the release of inflammatory mediators such as histamine, prostaglandins, leukotrienes, platelet activating factor (PAF) and chemotactic factors for monocytes, neutrophils and eosinophils. These mediators activate smooth muscle, causing bronchial constriction, and act on adjacent immune, epithelial and endothelial cells to facilitate and amplify the inflammatory response. The drugs currently available for treating asthma include the beta-adrenergics, corticosteroids, anti-leukotrienes, anti-cholinergics, xanthines and, less frequently non-steroidal anti-inflammatory drugs, (NSAIDS).
These drugs, when used properly, provide good management of asthma. A significant number of asthma sufferers, however are poorly controlled and a need for improved anti-asthmatic drug therapy remains.
Anti-inflammatory peptides derived from the salivary gland have been described previously. These include submandibular gland peptide-T (SGP-T), which inhibits lipopolysaccharide-induced hypotension at doses as low as 1 μg/kg (Mathison et al., (1997) Amer. J. Physiol., v. 273, p. R1017) and has also been shown to inhibit systemic and intestinal Type 1 hypersensitivity reactions (Befus et al., (1997) Int. Arch. Allergy Immunol., v. 113, p. 337; Mathison et al, (1997) supra and Proc. West Pharmacol. Soc., v. 40, p. 73). Further studies demonstrated that tripeptide or larger fragments of SGP-T also have significant anti-inflammatory activity (International Patent Application WO 98/06742).